Impact Of Irinotecan Dose Adjustment Based On UGT1A1 Genotype On The Toxicity And Efficacy Of FOLFIRI Regimen In Treating Patients With Metastatic Colorectal Cancer:A Prospective Study

Background and Objective FOLFIRI composed of Irinotecan(CPT-11),fluorouracil and leucovorin,which is one of the standard regimens for metastatic colorectal cancer(m CRC).Severe neutropenia and delayed-onset diarrhea limit the clinical application.Uridine diphosphate-glucuronate transferase 1A(UGT1A1)is the main inactivation enzyme of CPT-11 in human body.In Caucasians,patients with UGT1A1*28 homozygous mutation have higher risk of serious adverse events,which require dose reduction but without specific recommendation.In Asians,UGT1A1*6 has similar function compared with UGT1A1*28.In our previous study,we found that the concentration of AUCSN-38G/AUCSN-38 in patients with both UGT1A1*28and*6 mutations was about twice as that of patients with other genotypes.Based on the previous study,we conducted a prospective,nationwide,multicenter clinical trial in April 2012: Impact of Irinotecan Dose Adjustment Based on UGT1A1 Genotype on the Toxicity and Efficacy of FOLFIRI Regimen in Treating Metastatic Colorectal Cancer: a Prospective Study.Mehtods We conducted a multi-center,prospective clinical trial in 20 hospitals nationwide.All enrolled patients were confirmed by histology as metastatic colorectal cancer,and the UGT1A1*28 and *6 genotypes were detected before chemotherapy.According to the UGT1A1*28 and *6 genotypes,patients were divided into wild type(*1/*1),one-mutated site variants(*1/*28,*1/*6)and two-mutated site variants(*28/*28,*6/*6,*6/*28).Patients with wild type and one-mutated site variants were treated with standard dose(group A).Patients with two-mutated site variants was randomly assigned into two groups,one group was treated with dose-reduced FOLFIRI regimen(CPT-11 reduced 50%)(group B)and the other group was treated with standard dose of FOLFIRI(group C).Treatment continued until disease progression or unacceptable toxicity.Evaluation of adverse events was based on the NCI-CTC3.0 version and the efficacy was based on Response Evaluation Criteria in Solid Tumors 1.1(RECIST 1.1).Follow up the progression-free survival(PFS)and overall survival(OS)of patients,analyze the differences of toxicity and efficacy among three groups,and evaluate the feasibility of dose reduction of CPT-11 according to the genotypes.Result From April 2012 to November 2015,a total of 670 m CRC patients had assessed for eligibility and579 m CRC patients had signed informed consent and enrolled our study.Among them,268 patients were wild type(46.2%),259 patients were one-mutated site variants(44.8%),and 52 patients were two-mutated site variants(9.0%).A total of 542 patients eventually completed randomization and received at least one cycle of FOLFIRI regimen,in whom 497 patients were in group A,22 patients were in group B,and 23 patients were in group C.No significant differences were found in clinical characteristics between the three groups(p?0.05).The incidence of Grade 3-4 neutropenia presented a gradually increasing trend in group A to group C(16.9%~21.7%,P=0.773).The incidence of Grade 4 neutropenia was significant higher in group C than group A and B(group A vs group B vs group C:4.0% vs 4.5% vs 17.4%,P=0.029).The incidence of Grade 3-4 thrombocytopenia in three groups were 2.4%,4.5% and 0%,respectively(P=0.483),and the incidence of Grade 3-4 anemia in three groups were 1.8%,0% and 4.3%,respectively(P=0.583).The incidence of Grade 2-4 diarrhea presented a same gradually increasing trend,but without statistically significant differences(P=0.805).There's no significant difference among the three groups in the incidence of Grade 3-4 diarrhea(P=0.479).The incidence of Grade 2-4 elevated bilirubin in the three groups were 3.0%,9.0%,4.3%, respectively(P=0.165).The incidence of Grade 2-4 fatigue revealed a gradually increasing trend(29.6% vs 31.8% vs 34.8%,P=0.850).The incidence of Grade 3-4fatigue among the three groups were 11.5%,13.6%,and 21.7%,respectively(P=0.294).The incidence of Grade 2-4 nausea and vomiting in the three groups were25.4%,18.2%,and 34.8% respectively(P=0.434).The Response Rates(RR)of group A,group B,group C were 25.2%(125/497),22.7%(5/22)and 9.1%(2/23),respectively.Although group C had the lowest RR,there's no significant statistical difference amomg the three groups(P=0.197).The median progression free survival(PFS)in the three group was 6.13 months,6.83 months and 5.53 months respectively(P=0.975),and the overall survival(OS)was19.9months,14.0 months and 19.93 months(P=0.685).No significant differences were found among the three groups.We also analyzed pharmacokinetics data in 48 patients,in which 34 were in group A,10 in group B,and 4 in group C.By using AUCSN-38G/AUCSN-38 as the evaluation indicator of deactivation of CPT-11,the level of AUCSN-38G/AUCSN-38 in group A was 3times higher than that in the group B(3.01 vs 1.01,P=0.027).The level of AUCSN-38G/AUCSN-38 in group B and group C were similar(1.01 vs 1.75,P=0.888).Conclusion Patients with two-mutated site variants of UGT1A1*28 and *6 adapting standard FOLFIRI regimen could induce the risk of Grade 4 neutropenia and using half dosage of CPT-11 could reduce the risk significantly without influencing the efficacy and prognosis.The pharmacokinetic results indicated that the ratio of inactivated SN-38 in patients with two-mutated site variants was still significantly lower than patients with wild type or one-mutated site variants,it indicated that futher investigation on dose adjustment is needed.